Acyl derivatives of 4-hydroxy-2h-1-benzothiopyran-3-carboxamide 1,1-dioxide

ABSTRACT

Acyl derivatives of 4-hydroxy-2H-1-benzothiopyran-3-carboxamide 1,1-dioxide having the following structural formulas are disclosed:   WHEREIN R1 and R2 are hydrogen, alkyl, aryl, aralkyl, alkoxy, halogen, cyano, nitro, trifluoromethyl, and the like. These compounds are useful as anti-inflammatory agents.

United States Patent [191 Zinnes et al.

[ ACYL DERIVATIVES OF 4-HYDROXY-2H-l-BENZOTHIOPYRAN-3- CARBOXAMIDE1,1-DIOXIDE [75] Inventors: Harold Zinnes, Rockaway; Neil A.

Lindo, Chatham, both of NJ.

[73] Assignee: Warner-Lambert Company, Morris Plaines, NJ.

[22] Filed: Mar. 23, 1973 [21] Appl. No.: 344,380

[52] U.S. Cl. 260/327 TH, 260/244 R, 424/275,

424/248 [51] Int. Cl. A61k 27/00, C07d 65/08 [58] Field of Search260/327 TH [56] References Cited UNITED STATES PATENTS 3,769,292 l0/l973Zinnes et al. 260/294.8 C

Primary ExaminerHenry R. Jiles Assistant Examiner-C. M. S. JaisleAttorney, Agent, or Firm-Albert H. Graddis; Frank S. Chow 11] 3,835,156[451 Sept. 10, 1974 wherein R and R are hydrogen, alkyl, aryl, aralkyl,alkoxy, halogen, cyano, nitro, trifluoromethyl, and the like.

These compounds are useful as anti-inflammatory agents.

3 Claims, No Drawings ACYL DERIVATIVES OF such as water for injectionand compounded into sus- 4-l-IYDROXY-2H-l-BENZOTHIOPYRAN-3- pensionssuitable for parenteral administration.

CARBOXAMIDE 1, l-DIOXIDE According to the present invention, the abovecompounds are produced by the following reaction scheme:

(H) (|)II R1 00113 R2 2. B30001 R2 I II (Ri': so Z The present inventionrelates to acyl derivatives of a z 4-hydroxy-2l-I- l-benzothiopyran-3-carboxamide l l dioxide having the followingstructural formulas: 0

1. NaH l =0 CONH- I l R2 R1 2. COCzor R2 S02 ll) S02 IV 0 ll wherein Ris alkyl or aryl.

a bit, Referring now to the above scheme, a compound of l structure I issuccessivel treated with a base such as con y R2 R sodium hydride and anacid chloride in a solvent such 1 as dimethylformamide to form amonoacyl derivative so; of formula II. Diacyl derivatives such as IIIare formed In by heating I with an acid anhydride. 0 The cyclicderivatives of formula IV are formed as a ll result of an internaldiacylation reaction. This is 0 achieved by the treatment of I with abase such as so- I :0 R1 dium hydride followed by the addition of eitherphosgene (COCl or an alkylor aralkylchloroformate so. "(5 .59 1.) IV ina solvent such as dimethylformamide.

The starting material I is prepared as described in cowherein R and Rare hydrogen, alkyl, aryl, aralkyl, pending application Ser. No. 163,076filed July 15, alkoxy, halogen, cyano, nitro, trifluoromethyl, and the1971, now abandoned.

like. In the above definitions for R,, R and R alkyl and The compoundsof this invention are useful as antialkoxy have 1 to 7 carbon atoms suchas methyl, inflammatory agents for mammals, i.e. cats, dogs, monethyl,propyl, isopropyl and the like, aryl has 6 to 8 keys and the like. Forexample, when they are adminiscarbon atoms such as phenyl or tolyl, andaralkyl is tered orally or intraperitoneally to laboratory animals arylas defined substituted by an alkyl group as defined. such as rats, at adose of 25-200 mg/kg, they reduce the swelling in the paw which has beenpreviously induced To further illustrate the practice of this invention,the by injection of an irritant such as carrageenin. following examplesare included:

These compounds are indicated in conditions where the soft tissues areinflamed, such as rheumatoid arthri EXAMPLE 1 tis in mammals. A dose of25-200 mg/kg in several di- 000cm vided doses daily orally or byinjection is recom- A mended. This dose regimen may be varied dependingC0NHCBH5 on the weight, age, sex, and the species of the mammal J beingtreated.

In order to use these compounds, they are formulated 2 .W M withpharmaceutical diluents such as lactose and com-4-Hydroxy-2H-l-benzothiopyran-3-carboxanilide acpounded into dosageforms such as tablets. Alternaetate l,l-Dioxide. A slurry of 0.044 molof sodium hytively, they can be formulated with a sterile vehicle dridein 30 ml of dimethylformamide was cooled to 5 and a solution of 12.6 g(0.4 mol) of 4-hydroxy-2H-1- benzothiopyran-3-carboxanilide 1 1 -dioxidein 30 m1 of dimethylformamide was slowly added over a 15 minute period.When gas evolution had ceased, a solution of 3.4 ml of acetyl chloridein 10 ml of dimethylformamide was added and the reaction mixture wasstirred at room temperature for 1.5 hr. It was poured into ice watercontaining excess hydrochloric acid and the resulting precipitate wascollected and dissolved in dichloromethane. The solution was washed withwater, dried, and evaporated to dryness. The solid residue wasrecrystallized from methanol to give 7.8 g (55%) of product; mp152.5154.5. 1r:

W 3300, 1680, 1660 cm".

Anal. Calcd for C I-1 N 8: C, 60.49; H, 4.23; N, 3.92; S, 8.97. Found:C, 60.71; H, 4.37; N, 3.64; S, 9.03.

EXAMPLE 2 O C OCH:

COCHa AFO L v l775, 1715 cm, absence of NH band.

EXAMPLE 3 0 N aHs 3 ,4-Dihydro-3-phe nyl-2H,5 H- 1 -benzothiopyrano-[3,4-e][1,3]oxazine-2,4-dione 6,6-dioxide. To a cooled, stirred slurryof 0.022 mol of sodium hydride in 50 ml of dimethylformamide was slowlyadded a solution of 6.3 g (0.02 mol) of4-hydroxy-N-phenyl-2H-lbenzothiopyran-3-carboxamide 1,1-dioxide in 100ml of dimethylformamide. When gas evolution had ceased, a solution of3.6 g of hexylchloroformate in 25 ml of dimethylformamide was addedslowly with cooling. The mixture was stirred at room temperature for 1hour and poured into ice-water containing excess hydrochloric acid. Theresulting gummy precipitate was collected and dissolved indichloromethane. The solution was washed well with water, dried,evaporated to dryness, and the residue was dissolved in 600 ml ofmethanol. Concentration to a volume of 400 ml and cooling gave 3.7 g ofproduct; mp 208209.5. It gave a negative ferric chloride test and wasinsoluble in dilute aqueous sodium hydroxide.

O O Ra III in which R and R are hydrogen, alkyl of 1 to 7 carbon atoms,aryl of 6 to 8 carbon atoms, aralkyl in which alkyl is as defined andsubstituted by an alkyl group as defined, alkoxy of l to 7 carbon atoms,halogen, cyano, nitro and trifluoromethyl.

2. 4-Hydroxy-2H-1-benzothiopyran-3-carboxanilide acetate 1,1-dioxide.

3. N-Acetyl-4-hydroxy-2H- 1 -benzothiopyran-3- carboxanilide acetate 1 1-dioxide.

2. 4-Hydroxy-2H-1-benzothiopyran-3-carboxanilide acetate 1,1-dioxide. 3.N-Acetyl-4-hydroxy-2H-1-benzothiopyran-3-carboxanilide acetate1,1-dioxide.